Evidence continues to accumulate that immunological mechanisms are of central importance in atherogenesis. Our lab first demonstrated that oxidation-specific epitopes of oxidized LDL (OxLDL) are immunogenic and that adaptive and innate immune responses to these neoepitopes lead not only to proatherogenic but atheroprotective responses as well. Innate immune responses provide the first line of defense against pathogens, and of necessity its receptors are preformed and selected by conservation. Our recent work supports the hypothesis that innate immune responses to neoepitopes of OxLDL have been conserved because common oxidation-specific epitopes of OxLDL are also present on apoptotic cells and display molecular mimicry with epitopes on common pathogens. Thus, these innate responses were conserved to play important roles in homeostasis in general. The overall aim of this Project is to explore the consequences of innate immunological responses to oxidation-specific epitopes of OxLDL. We will specifically test the hypothesis that oxidation-specific epitopes are a major target of innate immunity in general, and of natural antibodies (NAbs) in particular, and that these NAbs play important roles in health and disease. Our Specific Aims are to test the following hypotheses: 1) That in mice, oxidation-specific epitopes are a major target of B-1 cell derived IgM NAbs, which play important roles in health (to clear apoptotic cells/apoptotic bodies and/or neutralize proinflammatory effects) and disease, (e.g. to block uptake of OxLDL and prevent atherogenesis). 2) That vital innate immune functions of B-1 cells, such as secretion of NAbs and cytokines, are regulated by ligation of pattern recognition receptors, (such as TLRs and CD36) as well as by nuclear receptors expressed in these cells (PPARg and delta), reflecting part of a primary integrated response of the innate immune network to inflammation and infection. 3) That oxidationspecific NAbs are also prevalent in humans and play similar important roles. In summary, in general these studies should provide an improved understanding of the role of innate immunity in atherogenesis and specifically define the role of oxidation-specific NAbs and the B-1 cells that secrete them in health and disease. Insights from these studies could lead to novel diagnostic and therapeutic options for patients with CVD and other inflammatory conditions.